**2. Pathology**

(age 1-day-old infants to 90-year-old adults),[15-16], the correlation of plaque appearance between B ultrasonography and pathology, [17] and the histological assessment in 281 carotid

In this connection, in a pioneer study we made a complete immunohistochemical characteri‐ zation in complicated carotid plaques. [18] The cellular components of carotid endarterectomy specimens were analyzed to assess their role in the pathogenesis of plaque rupture and intraplaque hemorrhage without rupture. The site of plaque rupture is associated with the presence of an extensive infiltrate of macrophages, T-lymphocytes, scarce B-lymphocytes, mast cells, and smooth muscle cells. Both the plaques showing these features and those with large amounts of lipid and thin fibrous caps, should be considered as "plaques at risk". Intraplaque hemorrhages without plaque rupture may be caused by the breakdown of neoformed vessels

This paper emphasized the importance of the detection of vulnerable plaque for preventing future cerebral events. The main factors in advanced plaque that are most likely to lead to complications are the thickness of the fibrous cap, the size of the necrotic core and intraplaque

Later on, we analyzed the relation between the anatomy of the carotid plaques and the presence of symptoms in 281 carotid endarterectomy specimens. [19] Almost 70% of plaque specimens demonstrated thrombus, intraplaque hemorrhage, or both. Thrombosis was observed in one fourth of specimens, and intraplaque hemorrhage in almost two thirds of specimens. Sixty four percent of plaques demonstrated neovascularization. In spite of findings in some published articles, [20] it was not possible to demonstrate that complicated plaques (plaque rupture, thrombosis, intraplaque hemorrhage) are associated with symptoms, and it appears that

Regarding the biology of the unstable atherosclerotic carotid plaque, an expression of c-fos,

On the other hand, MRI has excellent soft tissue contrast and is able to quantify carotid plaque size and composition with good accuracy and reproducibility and provides an opportunity to prospectively examine the relationship between plaque features and subsequent cerebrovas‐ cular events. [22] In a paper by Takaya et al [23] 154 patients with an asymptomatic 50% to 79% carotid stenosis by ultrasound with > or =12 months of follow-up were included for multicontrast-weighted carotid MRIs were included. Over a mean follow-up period of 38.2 months, arteries with thinned or ruptured fibrous caps, intraplaque hemorrhage, larger maximum %lipid-rich/necrotic cores, and larger maximum wall thickness were associated

MRI imaging techniques have permitted serial monitoring of atherosclerotic disease evolution

At last, based upon our research, carotid barochemoreceptor involvement in old patients who died from stroke and suffering obstructive carotid atheromatosis will be discussed. [24]

and the identification of intraplaque risk factors for accelerated progresión. [22]

endarterectomy specimens [18] will be widely described and discussed.

hemorrhage, and the extent of inflammatory activity within the plaque.

complicated plaques may occur at any time, irrespective of symptoms. [19]

with the occurrence of subsequent cerebrovascular events. [23]

in the core, base, and periphery of the plaques. [18]

32 Carotid Artery Disease - From Bench to Bedside and Beyond

p53 and PCNA was demonstrated by us. [21]

Carotid atherosclerosis is commonly associated with symptoms of cerebral ischemia. However little attention has been directed to intraplaque factors that precipitate the onset of symptoms. [25] On the other hand, the treatment of coronary and carotid atherosclerosis, requires an understanding of the pathogenesis of plaque fissure. [26] Advances in molecular biology, coronary diagnostic techniques and cardiac treatments have suggested new factors leading to plaque fissure. [26-28] It was suggested that the risk of plaque fissure depends on plaque composition rather than plaque size, because only plaques rich in soft extracellular lipids are prone to rupture. [27] Also, it was demonstrated that ruptured plaque caps have much larger transverse gradients of connective tissue constituents than non-ruptured plaque caps, and that the development of these transverse gradients may be critical in determining the propensity of a plaque to rupture. [28] It was also shown that the site of rupture of thrombosed coronary atherosclerotic plaques is marked by an inflammatory infiltration where the macrophages are the dominant cells. [29]

However, the exact mechanisms causing plaque rupture are yet not complete known. [29] In this connection, papers dealing with rupture of carotid plaque surface are few in spite of the growing importance of the subject. [18,19,30] We analyzed in pioneer papers[18,19,30] the cellular and vascular components of surgically excised carotid endarterectomies. Thus, the cell populations involved in the inflammatory activity in atherosclerotic lesions were further characterized with cell specific monoclonal antibodies in order to obtain information about their role in the pathogenesis of plaque rupture and intraplaque hemorrhage.[30] In brief, 76 surgical specimens of 74 patients who were submitted to carotid endarterectomy were used for these studies. There were 55 males and 19 females. Age ranged from 40 to 83 years (mean 69.4 years).Patients were divided into three clinical subgroups: asymptomatic (carotid lumen obstruction > 70%), symptomatic (stable) and symptomatic (unstable). The usual unifying pathologic feature in the plaques was the presence of large lipid cores with a fibrous cap overlying the lipid core and a band of fibrous tissue of varying thickness separating the plaque from the atrophic media (Figure 1). This collagen rim was in general extensively vascularized. Exceptionally the plaque was composed of fibrocellular tissue without a clear lipid core. In most cases, widespread chronic inflammatory infiltrates were observed either in the cap or in the lipid core (Figure 2). In all cases the carotid bifurcation and the first 1.5 cm of the internal carotid were involved.

The result of immunophenotyping of the cellular constituents of the plaques were described in relation to the different layers (from the lumen to the media), namely: Endothelial lining (Anti-CD31 and anti-CD34). The fibrous cap at the site of the rupture/erosion had an eroded surface characterized by loss of the endothelial lining (Figure 3). On the other hand in the remaining surface a continuous, not damaged row of endothelial cells stained with anti-CD31 and anti-CD34 was observed in all cases

**Fibrous cap:** the collagenous fibrous cap at the site of erosion was attenuated and the pheno‐ typic characterization of the cells showed inflammatory components consisting mainly of macrophages (CD68 positive), approximately 2/3 of the total infiltration (Figure 4). The remaining 1/3 was composed of T-lymphocytes and rare B-lymphocytes. This pattern was observed in 34/ 41 (83%) of ruptured plaques. A close interaction between macrophages and the abundant capillaries of the lipid cores (Figure 4) and macrophages and T-lymphocytes was commonly observed. Some foamy macrophages showed not only brown staining correspond‐ ing to the expression of CD68 but also weak red staining for CD31, thus suggesting that these cells also contain this adhesion molecule. Plaques "at risk" (attenuated fibrous cap, large lipid core and extensive macrophage infiltration) are represented in Figure 1.

**Figure 3.** Intraplaque hemorrhage without plaque rupture. Superimposed parietal thrombus. A continuous non rup‐ tured thick cap is shown (arrow). A parietal thrombus is implanted in an eroded surface (arrowhead), and a rich lipid core is heavily embedded by intraplaque hemorrhage(LC).Trichrome-stained collagen, *blue*; hemorrhage, *light red*;

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**Lipid cores:** two different types of lipid cores could be depicted, avascular or mildly vascu‐ larized lipid cores and highly vascularized, with neoformed vessels stained with CD34 and CD31(Figure 5 and 6). These vessels varied from proliferated small, thin walled blood vessels to bigger ones, in some cases presenting a hemangioma-like aspect. CD34 stained endothelia of all kind of vessels; conversely, neoformed vessels showed a weak stain with CD31.Tlymphocytes were found to be in contact with neoformed vessels, and in some cases, migrating

**Media:** this tunic was composed of 5 to 12 rows of smooth muscle cells, with their long axes oriented circumferentially, as the edge of the endarterectomy passed through that level. Some thin walled normal capillaries oriented longitudinally to the long axis of the smooth muscle cells were fairly showed by the CD34 and CD31 (Figure 8). Although this tunic did not belong to the plaque itself, it is herein described because of its peculiar vascularization. It is therefore necessary to make a clear distinction regarding the neoformed vessels of the base and periph‐ ery of the plaque, and the adjacent capillaries of the media originating from the vasavasorum. **Deeper layers of the plaque:** the base and the shoulder of the plaques showed in 28/76 cases neoformed vessels, thin or thick walled, CD34 positive (Figure 7), generally surrounded by

thrombus *blue-red* (original magnification \_200).

mild to extensive mononuclear infiltrates.

through the endothelial cells

**Figure 1.** A large lipid core with a thin fibrous cap (arrow) overlying the lipid core is observed.

**Figure 2.** A neoformed thin-walled vessel is shown with lymphocytes migrating to the highly vascularized lipid. Mag‐ nification ´250

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remaining 1/3 was composed of T-lymphocytes and rare B-lymphocytes. This pattern was observed in 34/ 41 (83%) of ruptured plaques. A close interaction between macrophages and the abundant capillaries of the lipid cores (Figure 4) and macrophages and T-lymphocytes was commonly observed. Some foamy macrophages showed not only brown staining correspond‐ ing to the expression of CD68 but also weak red staining for CD31, thus suggesting that these cells also contain this adhesion molecule. Plaques "at risk" (attenuated fibrous cap, large lipid

core and extensive macrophage infiltration) are represented in Figure 1.

34 Carotid Artery Disease - From Bench to Bedside and Beyond

**Figure 1.** A large lipid core with a thin fibrous cap (arrow) overlying the lipid core is observed.

**Figure 2.** A neoformed thin-walled vessel is shown with lymphocytes migrating to the highly vascularized lipid. Mag‐

nification ´250

**Figure 3.** Intraplaque hemorrhage without plaque rupture. Superimposed parietal thrombus. A continuous non rup‐ tured thick cap is shown (arrow). A parietal thrombus is implanted in an eroded surface (arrowhead), and a rich lipid core is heavily embedded by intraplaque hemorrhage(LC).Trichrome-stained collagen, *blue*; hemorrhage, *light red*; thrombus *blue-red* (original magnification \_200).

**Lipid cores:** two different types of lipid cores could be depicted, avascular or mildly vascu‐ larized lipid cores and highly vascularized, with neoformed vessels stained with CD34 and CD31(Figure 5 and 6). These vessels varied from proliferated small, thin walled blood vessels to bigger ones, in some cases presenting a hemangioma-like aspect. CD34 stained endothelia of all kind of vessels; conversely, neoformed vessels showed a weak stain with CD31.Tlymphocytes were found to be in contact with neoformed vessels, and in some cases, migrating through the endothelial cells

**Media:** this tunic was composed of 5 to 12 rows of smooth muscle cells, with their long axes oriented circumferentially, as the edge of the endarterectomy passed through that level. Some thin walled normal capillaries oriented longitudinally to the long axis of the smooth muscle cells were fairly showed by the CD34 and CD31 (Figure 8). Although this tunic did not belong to the plaque itself, it is herein described because of its peculiar vascularization. It is therefore necessary to make a clear distinction regarding the neoformed vessels of the base and periph‐ ery of the plaque, and the adjacent capillaries of the media originating from the vasavasorum.

**Deeper layers of the plaque:** the base and the shoulder of the plaques showed in 28/76 cases neoformed vessels, thin or thick walled, CD34 positive (Figure 7), generally surrounded by mild to extensive mononuclear infiltrates.

Basically atherosclerotic plaques were found to be-long to six different lesions, namely: plaque rupture plus thrombosis (18/76, 23.6%), plaque rupture plus intraplaque hemorrhage plus thrombosis (18/76, 23.6%), intraplaque hemorrhage without plaque rupture (16/76, 21.0%), plaque rupture plus intraplaque hemorrhage (5/76, 6.5%), stable calcified non complicated plaque (14/76, 18.4%) and unstable, soft, non complicated plaque (5/76, 6.5%). The first four lesions were considered as "complicated lesions".

**Figure 5.** Intense neovascularization of the lipid core. Immunoperoxidase technique for smooth muscle cells (α-actin). In panel A, the asterisk indicates a thick neovascularization vessel. Panel B shows the middle arterial layer. In panel C:,a central neoformed vessel outgrowth in "glove finger" is seen into the lipid core. Endothelial pyknotic cells surrounded

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**Figure 6.** Lipid-rich core is heavily vascularized by great number of thin-walled, neoformed,CD34-positive vessels.

Magnification ´250.

by scarse pericytes, macrophages, and lymphocytes in the periphery are shown.

**Figure 4.** Foamy macrophages show brown staining corresponding to the expression of CD68 and weak red staining for CD31.


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Basically atherosclerotic plaques were found to be-long to six different lesions, namely: plaque rupture plus thrombosis (18/76, 23.6%), plaque rupture plus intraplaque hemorrhage plus thrombosis (18/76, 23.6%), intraplaque hemorrhage without plaque rupture (16/76, 21.0%), plaque rupture plus intraplaque hemorrhage (5/76, 6.5%), stable calcified non complicated plaque (14/76, 18.4%) and unstable, soft, non complicated plaque (5/76, 6.5%). The first four

**Figure 4.** Foamy macrophages show brown staining corresponding to the expression of CD68 and weak red staining

**• Plaque rupture plus thrombosis (PR+T).** The fibrous cap overlying the lipid core was highly variable in thickness and cellular constituents. Plaques presented ulcerations with break‐ down of the surface of the cap. Their-regularity had a punched-out characteristic or was simply a tear with borders; in rare cases plaques contained virtually no fibrous cap. The rupture was covered by a thrombus, and in many cases the thrombus was found directly overlying the lipid core of the lesion, entering a large pool of extracellular lipids. As said the borders of the rupture presented a mononuclear infiltration with a high density of

**• Plaque rupture plus intraplaque hemorrhage plus thrombosis (PR+IPH+T).** (Figure 9)The histological findings were similar to the ruptured-thrombosed plaques, but there was also

extensive disruption of the plaque by an intraplaque hemorrhage.

lesions were considered as "complicated lesions".

36 Carotid Artery Disease - From Bench to Bedside and Beyond

for CD31.

macrophages.

**Figure 5.** Intense neovascularization of the lipid core. Immunoperoxidase technique for smooth muscle cells (α-actin). In panel A, the asterisk indicates a thick neovascularization vessel. Panel B shows the middle arterial layer. In panel C:,a central neoformed vessel outgrowth in "glove finger" is seen into the lipid core. Endothelial pyknotic cells surrounded by scarse pericytes, macrophages, and lymphocytes in the periphery are shown.

**Figure 6.** Lipid-rich core is heavily vascularized by great number of thin-walled, neoformed,CD34-positive vessels. Magnification ´250.

slitlike hemorrhages distant to the main lesion were found in 12 cases, in 5 of them without

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**Figure 9.** Plaque rupture (arrow) plus intraplaque hemorrhage and parietal thrombosis. An entire specimen from a carotid endarterectomy frontally cut is shown. 1, Common carotid artery; 2,external carotid artery. \*Large lipid core with huge intraplaque hemorrhage with thrombotic components, and small parietal thrombus are observed. Fibrous

**Figure 10.** Sample of carotid endarterectomy. Laminar hemorrhage, distal to the main lesion Trichrome-stained colla‐

the presence of a massive intraplaque hemorrhage.

cap is extremely thin (hematoxylin-eosin; original magnification 3).

gen, *blue*; hemorrhage, *light red*; Magnification ´250.

**Figure 7.** Vascularization of the shoulder of the plaque. Note thin-walled neoformed vessels of different shapes and sizes. Outer zone shows media and an extensive quantity of thin-walled normal capillaries,longitudinally oriented *(brown)*. Antiactin monoclonal antibody(HHF35) was used to demonstrate vascular structures (original magnification \_250).

**Figure 8.** Low magnification view of an entire endarterectomy specimen shows actin-positive vessel walls (HHF35) and hyperplastic smooth muscle cells (asterisc). Media (arrowheads) shows normal arrangement and at this level is composed of only 5 to 10 layers of smooth muscle cells (arrow). Magnification x25.

**Intraplaque hemorrhage without plaque rupture (IPH)** (Figure 10). None of them had a connection between the hemorrhage and the arterial lumen, in spite of a careful search in serial sections. Conversely the intimal surfaces were clean and none showed evidence or platelet or fibrin deposition. Hemorrhages varied from microscopic, microfocal or slitlike foci of recent hemorrhage, with no evident changes in the overall makeup of the plaque to massive hemor‐ rhage, elevation and disruption of the intima to massive hemorrhage,elevation and disruption of the intima and occlusive stenosis. Only these massive lesions were considered. Of note, slitlike hemorrhages distant to the main lesion were found in 12 cases, in 5 of them without the presence of a massive intraplaque hemorrhage.

**Figure 7.** Vascularization of the shoulder of the plaque. Note thin-walled neoformed vessels of different shapes and sizes. Outer zone shows media and an extensive quantity of thin-walled normal capillaries,longitudinally oriented *(brown)*. Antiactin monoclonal antibody(HHF35) was used to demonstrate vascular structures (original magnification

**Figure 8.** Low magnification view of an entire endarterectomy specimen shows actin-positive vessel walls (HHF35) and hyperplastic smooth muscle cells (asterisc). Media (arrowheads) shows normal arrangement and at this level is

**Intraplaque hemorrhage without plaque rupture (IPH)** (Figure 10). None of them had a connection between the hemorrhage and the arterial lumen, in spite of a careful search in serial sections. Conversely the intimal surfaces were clean and none showed evidence or platelet or fibrin deposition. Hemorrhages varied from microscopic, microfocal or slitlike foci of recent hemorrhage, with no evident changes in the overall makeup of the plaque to massive hemor‐ rhage, elevation and disruption of the intima to massive hemorrhage,elevation and disruption of the intima and occlusive stenosis. Only these massive lesions were considered. Of note,

composed of only 5 to 10 layers of smooth muscle cells (arrow). Magnification x25.

\_250).

38 Carotid Artery Disease - From Bench to Bedside and Beyond

**Figure 9.** Plaque rupture (arrow) plus intraplaque hemorrhage and parietal thrombosis. An entire specimen from a carotid endarterectomy frontally cut is shown. 1, Common carotid artery; 2,external carotid artery. \*Large lipid core with huge intraplaque hemorrhage with thrombotic components, and small parietal thrombus are observed. Fibrous cap is extremely thin (hematoxylin-eosin; original magnification 3).

**Figure 10.** Sample of carotid endarterectomy. Laminar hemorrhage, distal to the main lesion Trichrome-stained colla‐ gen, *blue*; hemorrhage, *light red*; Magnification ´250.

**Plaque rupture plus intraplaque hemorrhage (PR+IPH)** (Figure 11). It was characterized by an extensive hemorrhage within the plaque with separation of its varying components and disruption of the intima.

**Unstable, soft, non complicated plaque (U+NC).** These plaques consisted of thin fibrous caps covering a lipid-rich core with extensive vascularization. As these are the ingredients of a plaque "at risk", those may be plaques in which rupture hemorrhage and/or thrombosis might

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**Complicated vs stable calcified, non complicated plaques.**Complicated plaques presented neoformed vessels in the periphery, shoulder and base of the plaque in 22/57 (38.5%) cases. Conversely only 1/14 (7.1%) of non complicated, stable calcified plaques presented this type of vessels (p < 0.05). Of note, the 5 cases of unstable, soft non complicated plaque presented neoformed vessels surrounding the plaque. In 10/57 (17.5%) complicated plaques unequivocal histological signs of old hemorrhages were found surrounding those vessels. Irrespective of presenting no rupture, 11/35 plaques showed a mononuclear in-filtrate in the fibrous cap. **Clinical-pathological correlation.** The risk factor variables (age, gender, hypertension, left ventricular hypertrophy, diabetes, weight, smoking and uric acid) could not be correlated with any of the pathological and immunohistochemical findings. Hypertension (70%) and smoking (59%) were the risk factors more frequently found irrespective of the morphological find‐ ings.Therefore, carotid endarterectomies provided the material for phenotypic characteriza‐ tion of vascular and cellular components of the plaque. This permitted to known the topography and the distribution of mononuclear infiltrates as well as endothelial cells. Although the cellular composition of advanced atherosclerotic plaques is known to be

**Intimal plaque rupture-inflammatory process.** We demonstrated for the first time[30] that rupture of carotid plaques is characterized by the presence of a macrophagic infiltration of the caps. The presence of a large number of foamy macrophages in plaque fissuring in human coronary thrombosis had been reported previously [29,32-34] and it was suggested that inflammation through enzymatic degradation of the fibrous cap by macrophages might destabilize the plaque, causing weakening at the immediate site of rupture. In carotid endar‐ terectomies although the fibrous cap overlying the plaque was variable in thickness, the area of rupture was dominated by macrophages as the main cellular component, T-lymphocytes and scarce B-lymphocytes and granulated and/or degranulated mast cells. Complete rupture of the fibrous cap was found to be the cause of thrombosis in 18 cases, intraplaque hemorrhage plus thrombosis in 18 and intraplaque hemorrhage in 5 cases. It means that approximately 50% of carotid endarterectomies have the plaque fissure as the anatomic substratum. Of note, only 23/41 (56%) of these cases have been symptomatic. Our studies in carotid plaques showed direct apposition of T-lymphocytes to macrophages and a close relation of these cells to endothelial cells. This highly suggests a cell-to-cell interaction, which results in an inflamma‐ tory process mediated by cellular adhesion molecules (such as CD31), cytokines, growth factors and other substances as described in coronary arteries[29] and aorta. [35] Therefore,

the possibility of autocrine, juxtacrine or paracrine secretion was evident. [36]

**Intraplaque hemorrhage without plaque rupture-plaque vascularization.** Intraplaque hemorrhage without rupture was present in 21% of the endarterectomies. This subset of carotid lesions was not related to cap erosion, but to plaque vascularization. Most lipid cores were highly vascularized with neoformed vessels with macrophages and T-cells in close contact and

have occurred in the future.

heterogeneous, [31] it can be summarized as:

**Figure 11.** Plaque rupture. A intraplaque hemorrhage (arrow ) B-. Breakdown of cap is clearly shown (between arrow‐ heads)

**• Stable, calcified, non complicated plaque (S+C)** (Figure 12).These plaques contained neither thrombosis nor hemorrhages and consisted of laminated fibrous connective tissue and irregular masses of calcified material. These areas appeared as acellular, roughly circular masses of pale-staining debris.

**Figure 12.** Stable calcified plate. Lipid core (1), thick cover (2), and abundant calcified areas in black

**Unstable, soft, non complicated plaque (U+NC).** These plaques consisted of thin fibrous caps covering a lipid-rich core with extensive vascularization. As these are the ingredients of a plaque "at risk", those may be plaques in which rupture hemorrhage and/or thrombosis might have occurred in the future.

**Plaque rupture plus intraplaque hemorrhage (PR+IPH)** (Figure 11). It was characterized by an extensive hemorrhage within the plaque with separation of its varying components and

**Figure 11.** Plaque rupture. A intraplaque hemorrhage (arrow ) B-. Breakdown of cap is clearly shown (between arrow‐

**• Stable, calcified, non complicated plaque (S+C)** (Figure 12).These plaques contained neither thrombosis nor hemorrhages and consisted of laminated fibrous connective tissue and irregular masses of calcified material. These areas appeared as acellular, roughly

**Figure 12.** Stable calcified plate. Lipid core (1), thick cover (2), and abundant calcified areas in black

disruption of the intima.

40 Carotid Artery Disease - From Bench to Bedside and Beyond

heads)

circular masses of pale-staining debris.

**Complicated vs stable calcified, non complicated plaques.**Complicated plaques presented neoformed vessels in the periphery, shoulder and base of the plaque in 22/57 (38.5%) cases. Conversely only 1/14 (7.1%) of non complicated, stable calcified plaques presented this type of vessels (p < 0.05). Of note, the 5 cases of unstable, soft non complicated plaque presented neoformed vessels surrounding the plaque. In 10/57 (17.5%) complicated plaques unequivocal histological signs of old hemorrhages were found surrounding those vessels. Irrespective of presenting no rupture, 11/35 plaques showed a mononuclear in-filtrate in the fibrous cap.

**Clinical-pathological correlation.** The risk factor variables (age, gender, hypertension, left ventricular hypertrophy, diabetes, weight, smoking and uric acid) could not be correlated with any of the pathological and immunohistochemical findings. Hypertension (70%) and smoking (59%) were the risk factors more frequently found irrespective of the morphological find‐ ings.Therefore, carotid endarterectomies provided the material for phenotypic characteriza‐ tion of vascular and cellular components of the plaque. This permitted to known the topography and the distribution of mononuclear infiltrates as well as endothelial cells. Although the cellular composition of advanced atherosclerotic plaques is known to be heterogeneous, [31] it can be summarized as:

**Intimal plaque rupture-inflammatory process.** We demonstrated for the first time[30] that rupture of carotid plaques is characterized by the presence of a macrophagic infiltration of the caps. The presence of a large number of foamy macrophages in plaque fissuring in human coronary thrombosis had been reported previously [29,32-34] and it was suggested that inflammation through enzymatic degradation of the fibrous cap by macrophages might destabilize the plaque, causing weakening at the immediate site of rupture. In carotid endar‐ terectomies although the fibrous cap overlying the plaque was variable in thickness, the area of rupture was dominated by macrophages as the main cellular component, T-lymphocytes and scarce B-lymphocytes and granulated and/or degranulated mast cells. Complete rupture of the fibrous cap was found to be the cause of thrombosis in 18 cases, intraplaque hemorrhage plus thrombosis in 18 and intraplaque hemorrhage in 5 cases. It means that approximately 50% of carotid endarterectomies have the plaque fissure as the anatomic substratum. Of note, only 23/41 (56%) of these cases have been symptomatic. Our studies in carotid plaques showed direct apposition of T-lymphocytes to macrophages and a close relation of these cells to endothelial cells. This highly suggests a cell-to-cell interaction, which results in an inflamma‐ tory process mediated by cellular adhesion molecules (such as CD31), cytokines, growth factors and other substances as described in coronary arteries[29] and aorta. [35] Therefore, the possibility of autocrine, juxtacrine or paracrine secretion was evident. [36]

**Intraplaque hemorrhage without plaque rupture-plaque vascularization.** Intraplaque hemorrhage without rupture was present in 21% of the endarterectomies. This subset of carotid lesions was not related to cap erosion, but to plaque vascularization. Most lipid cores were highly vascularized with neoformed vessels with macrophages and T-cells in close contact and some cases disrupting the endothelium The abrupt growing of the lipid cores and/or an overproduction of oxygen free radicals could lead to the breakdown of core vessels and intraplaque hemorrhage. This seems to be the most plausible mechanism. The periphery and shoulder of the plaques had in 30% of the cases neoformed vessels surrounded by extensive mononuclear infiltrates. Theseneoformed vessels showed a weak stain with CD31. Consider‐ ing that CD31 (PECAM-1) is a molecular adhesion molecule, the lack of expression could be pointing out a functional difference between normal and neoformed vessels. PECAM- 1 is required for transendothelial migration of leucocytes.

For statistical purposes, plaques were divided into two subsets: **complicated** (types PR+T, PR +IPH+T, PR+IPH, ulcerated calcified plaques and IPH) vs. **non-complicated**, and **ruptured**

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Complicated plaques (205 of 281) exhibited mononuclear infiltrates in the periphery, should‐ ers,and bases in 137 of 205 (67%) plaques, compared with only 22 of 76 (29%) noncomplicated plaques (p< 0.001). Complicated plaques demonstrated neoformed vessels in the periphery, shoulders, and bases in 146 of 205 (71%) plaques, compared with only 38 of 76 (50%) noncom‐ plicated plaques (p<0.001). Twelve of 18 unstable, soft, non complicated plaques exhibited neoformed vessels surrounding the plaques. The remaining 6 plaques had huge lipid cores without evident neoformed vessels, suggesting very recent development. In 34 of 205(17%) complicated plaques, old hemorrhages were found surrounding neoformedvessels. Ruptured versus non-ruptured plaques. Infiltrates were noted in the caps and shoulders in 108 of 130 (83%) ruptured plaques and 22 of 151 (15%) unruptured plaques (p< 0.0001).External carotid arteries arteries exhibited typical histopathologic findings of advanced atheromatosis in 51 of 281 cases(18%).Only 2 of 51 affected cases demonstrated complicated plaques.This resulted in a significant difference when compared with the internal carotid artery ruptures (1of40 vs 85 of 165 p< 0.001).Risk factors could not be associated with any pathologic findings. Hyperten‐ sion (74%), smoking (61%), hyperlipidemia (61%), and diabetes mellitus (24%) were the risk factors most frequently noted. No correlation could be established between plaque type and symptoms (Table I). Of note, although 99 of 205 (48%) complicated plaques were found in patients with symptomatic disease, a high percentage (106 of 205, 52%) were also found in patients with asymptomatic disease. The same was observed for ruptured plaques; 67 of 130 (52%) were found in patients with symptomatic disease, compared with 63 of 130 (48%) in patients with asymptomatic disease. No relation could be found between symptomatic versus asymptomatic disease with regard to old hemorrhage (18 [12%] vs 26 [19%]), distal IPH(19 [13%] vs 13 [10%]), laminar hemorrhage (14 [9%] vs 22 [16%]), and parietal thrombosis (14 [9%]

Differences in flow velocity profiles and wall shear stress might explain the lower atheroscler‐ otic involvement and rare complications of the external carotid artery as compared with the internal carotid artery (205 of 281 vs 2 of 281; P<0.0001). Areas of carotid plaque rupture were characterized by macrophagic infiltration at the rupture. This finding suggests that inflam‐ mation, through enzymatic degradation of the fibrous cap by macrophages, might destabilize the plaque, causing weakening at the site of rupture.[25,30,40] Complete rupture of the cap (46% of cases) was the cause of thrombosis in 7%, IPH plus thrombosis in 18%, and IPH in 19%. Therefore plaque rupture was the cause of thrombosis in only 25% of cases. Many factors can modulate the development of thrombus. Long-term preoperative administration of aspirin and use of heparin during surgery may explain the relatively low frequency of thrombosis observed in ruptured plaques. Other possibilities are that fibrin or platelet deposition was missed at previous embolization orduring microscopic examination because of sampling. However, inasmuch as excisionwas *in bloc*, without "touching" the lesion, thrombus displace‐ ment seems unlikely. IPH without rupture represented 27% of endarterectomy specimens in the present study. This subset of lesions was not related to rupture of the cap, but to plaque

(types 1 through 4) vs **non-ruptured** (types IPH,S+C and U+NC).

vs18 [13%]).

The same mechanism postulated for the vessels of the core may operate in neoformed vessels. The presence of histological signs of old hemorrhages and the existence of slitlike hemorrhages at that level strongly suggest that a local origin of bleeding may operate. Lusby et al[25] demonstrated that the resultant angiogenesis associated with hemorrhages might make those lesions prone to mechanical stress and subsequent hemorrhages. Accordingly, our observa‐ tions and those by other authors suggest that intraplaque hemorrhages may occur at any time in the history of carotid plaque. [37] Hypertension may be a predisposing factor in the rupture of neoformed vessels and the development of the hemorrhage within the plaque.

Our results in 76 endarterectomies suggest that the site of plaque rupture is associated with the presence of a large macrophagic infiltration, [38] as well as T-lymphocytes rare B-lympho‐ cytes and mast cells and lack of smooth muscle cells. These peculiar type of plaque should be considered as a "plaque at risk"[29] in addition to plaques containing large amounts of lipid pools and a thin fibrous cap. [34] Conversely, intraplaque hemorrhages without plaque rupture might be due to the breakdown of neo-formed core vessels and/or neoformed vessels of the base and shoulder of the plaque.

The decision of whether to perform endarterectomy in patients with asymptomatic disease should be made on the basis of data including degree of stenosis and activity of the carotid lesion, as well as issues of medical and surgical morbidity. [39]

**The relationship between anatomy of carotid plaques and the presence or not of symp‐ toms.** For this purpose we carried out an investigation[19] in order to analyze in a large sample the relation between the anatomy of carotid plaques and the presence of symptoms in 281 endarterectomy specimens. To avoid an excessive number of plaque subtypes that might blur the relationship with symptoms, [31] only complicated and non-complicated plaques and ruptured and nonruptured plaques were used for statistical analysis. Patients (mean age, 68 +/-8 y.o.,range,40-84 y.o.) were 213 men (mean age, 68 y.o.s; range, 45-83 y.o.) and 68 women (mean age,68.7 y.o.; range, 40-84 y.o.).[19] In all cases the bifurcation and the first 10 to 15 mm of the internal carotid artery were involved. In 196 plaques, large lipid cores with a fibrous cap and a band of fibrous tissue separating the plaque from the remainder of the media were observed. The cap was frequently vascularized. In most cases, extensive inflammatory infiltrates consisting of macrophages, smaller numbers of T lymphocytes, a few B lymphocytes, and mast cells were observed. In the remaining cases, the plaque was composed of fibrocellular tissue only.[19]

For statistical purposes, plaques were divided into two subsets: **complicated** (types PR+T, PR +IPH+T, PR+IPH, ulcerated calcified plaques and IPH) vs. **non-complicated**, and **ruptured** (types 1 through 4) vs **non-ruptured** (types IPH,S+C and U+NC).

some cases disrupting the endothelium The abrupt growing of the lipid cores and/or an overproduction of oxygen free radicals could lead to the breakdown of core vessels and intraplaque hemorrhage. This seems to be the most plausible mechanism. The periphery and shoulder of the plaques had in 30% of the cases neoformed vessels surrounded by extensive mononuclear infiltrates. Theseneoformed vessels showed a weak stain with CD31. Consider‐ ing that CD31 (PECAM-1) is a molecular adhesion molecule, the lack of expression could be pointing out a functional difference between normal and neoformed vessels. PECAM- 1 is

The same mechanism postulated for the vessels of the core may operate in neoformed vessels. The presence of histological signs of old hemorrhages and the existence of slitlike hemorrhages at that level strongly suggest that a local origin of bleeding may operate. Lusby et al[25] demonstrated that the resultant angiogenesis associated with hemorrhages might make those lesions prone to mechanical stress and subsequent hemorrhages. Accordingly, our observa‐ tions and those by other authors suggest that intraplaque hemorrhages may occur at any time in the history of carotid plaque. [37] Hypertension may be a predisposing factor in the rupture

Our results in 76 endarterectomies suggest that the site of plaque rupture is associated with the presence of a large macrophagic infiltration, [38] as well as T-lymphocytes rare B-lympho‐ cytes and mast cells and lack of smooth muscle cells. These peculiar type of plaque should be considered as a "plaque at risk"[29] in addition to plaques containing large amounts of lipid pools and a thin fibrous cap. [34] Conversely, intraplaque hemorrhages without plaque rupture might be due to the breakdown of neo-formed core vessels and/or neoformed vessels

The decision of whether to perform endarterectomy in patients with asymptomatic disease should be made on the basis of data including degree of stenosis and activity of the carotid

**The relationship between anatomy of carotid plaques and the presence or not of symp‐ toms.** For this purpose we carried out an investigation[19] in order to analyze in a large sample the relation between the anatomy of carotid plaques and the presence of symptoms in 281 endarterectomy specimens. To avoid an excessive number of plaque subtypes that might blur the relationship with symptoms, [31] only complicated and non-complicated plaques and ruptured and nonruptured plaques were used for statistical analysis. Patients (mean age, 68 +/-8 y.o.,range,40-84 y.o.) were 213 men (mean age, 68 y.o.s; range, 45-83 y.o.) and 68 women (mean age,68.7 y.o.; range, 40-84 y.o.).[19] In all cases the bifurcation and the first 10 to 15 mm of the internal carotid artery were involved. In 196 plaques, large lipid cores with a fibrous cap and a band of fibrous tissue separating the plaque from the remainder of the media were observed. The cap was frequently vascularized. In most cases, extensive inflammatory infiltrates consisting of macrophages, smaller numbers of T lymphocytes, a few B lymphocytes, and mast cells were observed. In the remaining cases, the plaque was composed of fibrocellular

of neoformed vessels and the development of the hemorrhage within the plaque.

required for transendothelial migration of leucocytes.

42 Carotid Artery Disease - From Bench to Bedside and Beyond

of the base and shoulder of the plaque.

tissue only.[19]

lesion, as well as issues of medical and surgical morbidity. [39]

Complicated plaques (205 of 281) exhibited mononuclear infiltrates in the periphery, should‐ ers,and bases in 137 of 205 (67%) plaques, compared with only 22 of 76 (29%) noncomplicated plaques (p< 0.001). Complicated plaques demonstrated neoformed vessels in the periphery, shoulders, and bases in 146 of 205 (71%) plaques, compared with only 38 of 76 (50%) noncom‐ plicated plaques (p<0.001). Twelve of 18 unstable, soft, non complicated plaques exhibited neoformed vessels surrounding the plaques. The remaining 6 plaques had huge lipid cores without evident neoformed vessels, suggesting very recent development. In 34 of 205(17%) complicated plaques, old hemorrhages were found surrounding neoformedvessels. Ruptured versus non-ruptured plaques. Infiltrates were noted in the caps and shoulders in 108 of 130 (83%) ruptured plaques and 22 of 151 (15%) unruptured plaques (p< 0.0001).External carotid arteries arteries exhibited typical histopathologic findings of advanced atheromatosis in 51 of 281 cases(18%).Only 2 of 51 affected cases demonstrated complicated plaques.This resulted in a significant difference when compared with the internal carotid artery ruptures (1of40 vs 85 of 165 p< 0.001).Risk factors could not be associated with any pathologic findings. Hyperten‐ sion (74%), smoking (61%), hyperlipidemia (61%), and diabetes mellitus (24%) were the risk factors most frequently noted. No correlation could be established between plaque type and symptoms (Table I). Of note, although 99 of 205 (48%) complicated plaques were found in patients with symptomatic disease, a high percentage (106 of 205, 52%) were also found in patients with asymptomatic disease. The same was observed for ruptured plaques; 67 of 130 (52%) were found in patients with symptomatic disease, compared with 63 of 130 (48%) in patients with asymptomatic disease. No relation could be found between symptomatic versus asymptomatic disease with regard to old hemorrhage (18 [12%] vs 26 [19%]), distal IPH(19 [13%] vs 13 [10%]), laminar hemorrhage (14 [9%] vs 22 [16%]), and parietal thrombosis (14 [9%] vs18 [13%]).

Differences in flow velocity profiles and wall shear stress might explain the lower atheroscler‐ otic involvement and rare complications of the external carotid artery as compared with the internal carotid artery (205 of 281 vs 2 of 281; P<0.0001). Areas of carotid plaque rupture were characterized by macrophagic infiltration at the rupture. This finding suggests that inflam‐ mation, through enzymatic degradation of the fibrous cap by macrophages, might destabilize the plaque, causing weakening at the site of rupture.[25,30,40] Complete rupture of the cap (46% of cases) was the cause of thrombosis in 7%, IPH plus thrombosis in 18%, and IPH in 19%. Therefore plaque rupture was the cause of thrombosis in only 25% of cases. Many factors can modulate the development of thrombus. Long-term preoperative administration of aspirin and use of heparin during surgery may explain the relatively low frequency of thrombosis observed in ruptured plaques. Other possibilities are that fibrin or platelet deposition was missed at previous embolization orduring microscopic examination because of sampling. However, inasmuch as excisionwas *in bloc*, without "touching" the lesion, thrombus displace‐ ment seems unlikely. IPH without rupture represented 27% of endarterectomy specimens in the present study. This subset of lesions was not related to rupture of the cap, but to plaque neovascularization. Lipid cores were highly vascularized with heterogeneous neoformed vessels and with macrophages and T cells in close contact with the endothelial wall. An increase in the amount of lipid in the core, mechanicalstresses,[25] and overproduction of oxygen free radicals by macrophages could lead to breakdown of core neoform vessels and IPH production.[27] The same mechanisms might also act in neoform vessels in the periphery of the plaques. Old hemorrhages in 17% of complicated plaques and presence of distant slitlike hemorrhages strongly suggest that the bleeding may be of local origin.[30,41] Hemorrhages were attributed to mechanical stress of turbulent flow and to wall vibration secondary to stiffness of the carotid wall,[30] and have also been associated with an increase in matrix metalloproteinase 1 expression in the macrophages of the fibrous cap, suggesting a role for inflammatory mediators in vessel disruption.[31] Therefore, IPH may occur at any time in the course of a carotid plaque.[18,30,37,38]

symptomatic plaques typically have large necrotic cores within the carotid arteries.[31] Some studies indicate that the association of complicated plaque and symptomatic disease does not exist.[55,62-64] It is conceivable that patients presumed to have no symptoms might have had embolic episodes and that emboli became impacted in silent cerebral areas or occurred during sleep.[25,37,44,57] Also, symptoms may not be recalled by patients, who are often elderly or frail. Of note, in a high-risk subgroup of patients with asymptomatic carotid stenosis the annual stroke rate was more than 4%.[33] Inzitari et al[10] confirmed that cardioembolic and small vessel stroke can occur, in addition to large vessel athero‐ thrombotic stroke, in patients with asymptomatic carotid stenosis. Finally, NASCET[3] demonstrated that most carotid strokes occur without warning symptoms, and only 5% to 15% of patients have a transient ischemic attack as an impending symptom of stroke. Nevertheless nowadays carotid endarterectomy or stenting should not be performed in asymptomatic patients except those in which some clinical conditions are present, as recommended by the American Heart Association/American Stroke Association. [65]

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Patients with asymptomatic carotid artery stenosis should be screened for other treatable risk factors for stroke with institution of appropriate lifestyle changes and medical therapy

**1.** Selection of asymptomatic patients for carotid revascularization should be guided by an assessment of comorbid conditions and life expectancy, as well as other individual factors, and should include a thorough discussion of the risks and benefits of the procedure with

**2.** The use of aspirin in conjunction with carotid endarterectomy (CEA) is recommended unless contraindicated because aspirin was used in all of the cited trials of CEA as an

**3.** Prophylactic CEA performed with <3% morbidity and mortality can be useful in highly selected patients with an asymptomatic carotid stenosis (minimum 60% by angiography, 70% by validated Doppler ultrasound) (Class IIa; Level of Evidence A). It should be noted that the benefit of surgery may now be lower than anticipated based on randomized trial results, and the cited 3% threshold for complication rates may be high because of interim

**4.** Prophylactic carotid artery stenting (CAS) might be considered in highly selected patients with an asymptomatic carotid stenosis (≥60% on angiography, ≥70% on validated Doppler ultrasonography, or ≥80% on computed tomographic angiography or MRA if the stenosis on ultrasonography was 50% to 69%). The advantage of revascularization over current

**5.** The usefulness of CAS as an alternative to CEA in asymptomatic patients at high risk for

**6.** Population screening for asymptomatic carotid artery stenosis is not recommended (Class

medical therapy alone is not well established (Class IIb; Level of Evidence B).

the surgical procedure is uncertain (Class IIb; Level of Evidence C).

an understanding of patient preferences (Class I; Level of Evidence C).

antiplatelet drug (Class I; Level of Evidence C).

(Class I; Level of Evidence C).

advances in medical therapy.

III; Level of Evidence B).

**Complicated and noncomplicated plaques versus symptomatic and asymptomatic disease.** Plaque rupture was present in 46% of endarterectomy specimens. However, only 67 of 130 (52%) of these were found in patients with symptomatic disease. On the other hand, a high proportion of patients with asymptomatic disease (48%) demonstrated complicated plaques.Coronary plaque ruptures have been identified in patients who died of noncar‐ diac causes.[18] Accordingly, occurrence of carotid plaque rupture or hemorrhage with‐ out symptomatic manifestation seems likely.The frequency of plaque hemorrhage and plaque disruption varied greatly among the various series from both symptomatic and asymptomatic specimens In a review of several studies,[25,37,42-46] Fisher et al observed that the pooled frequency of plaque hemorrhage and rupture demonstrated a significant‐ ly increased frequency in the symptomatic group. However,pooling data from multiple sources when methods of analysis are different (histologicvs macroscopic) is hazardous. [47] Therefore studies in which only macroscopic assessment was performed[25,37,48-53] must be discarded. Some authors stress that IPH indicates only the severity of atherosclero‐ sis;[50,51,54-57] others suggest IPH has a direct role in pathogenesis of transient ischemic attack or stroke. [25,35,44,46,57] When most studies are considered, the incidence of IPH in symptomatic and asymptomatic disease spreads considerably In the symptomatic group, incidence varied from 17% to 97%, compared with 2% to 91% in the asymptomatic group. In the European Carotid Plaque Study, [58] a high incidence of IPH was observed in symptomatic (94%) and asymptomatic (71%) groups A higher incidence of IPH was reported in patients without symptoms.[55,59,60] Lennihan et al[54] scored the occurrence of IPH only in patients with symptoms, and found ipsilateral symptoms in 57% of patients with IPH and 65% of patients without IPH, indicating little difference between the two groups. IPH seems to be more common in plaques causing high-grade stenosis.[47,54,55] Carr et al[52] found patients with symptomatic plaques to have more frequent plaque rupture, fibrous cap thinning, and cap foam cell infiltration, compared with patients with asympto‐ matic plaques. IPH was also seen in all specimens from symptomatic specimens and in 68% of asymptomatic specimens. However, this study included too few patients to be signifi‐ cant. Despite a close relationship between IPH and symptoms,[37,61-63] and carotid plaque rupture, thrombosis, and symptoms, [25,60,61] it has also been claimed that patients with symptomatic plaques typically have large necrotic cores within the carotid arteries.[31] Some studies indicate that the association of complicated plaque and symptomatic disease does not exist.[55,62-64] It is conceivable that patients presumed to have no symptoms might have had embolic episodes and that emboli became impacted in silent cerebral areas or occurred during sleep.[25,37,44,57] Also, symptoms may not be recalled by patients, who are often elderly or frail. Of note, in a high-risk subgroup of patients with asymptomatic carotid stenosis the annual stroke rate was more than 4%.[33] Inzitari et al[10] confirmed that cardioembolic and small vessel stroke can occur, in addition to large vessel athero‐ thrombotic stroke, in patients with asymptomatic carotid stenosis. Finally, NASCET[3] demonstrated that most carotid strokes occur without warning symptoms, and only 5% to 15% of patients have a transient ischemic attack as an impending symptom of stroke. Nevertheless nowadays carotid endarterectomy or stenting should not be performed in asymptomatic patients except those in which some clinical conditions are present, as recommended by the American Heart Association/American Stroke Association. [65]

neovascularization. Lipid cores were highly vascularized with heterogeneous neoformed vessels and with macrophages and T cells in close contact with the endothelial wall. An increase in the amount of lipid in the core, mechanicalstresses,[25] and overproduction of oxygen free radicals by macrophages could lead to breakdown of core neoform vessels and IPH production.[27] The same mechanisms might also act in neoform vessels in the periphery of the plaques. Old hemorrhages in 17% of complicated plaques and presence of distant slitlike hemorrhages strongly suggest that the bleeding may be of local origin.[30,41] Hemorrhages were attributed to mechanical stress of turbulent flow and to wall vibration secondary to stiffness of the carotid wall,[30] and have also been associated with an increase in matrix metalloproteinase 1 expression in the macrophages of the fibrous cap, suggesting a role for inflammatory mediators in vessel disruption.[31] Therefore, IPH may occur at any time in the

**Complicated and noncomplicated plaques versus symptomatic and asymptomatic disease.** Plaque rupture was present in 46% of endarterectomy specimens. However, only 67 of 130 (52%) of these were found in patients with symptomatic disease. On the other hand, a high proportion of patients with asymptomatic disease (48%) demonstrated complicated plaques.Coronary plaque ruptures have been identified in patients who died of noncar‐ diac causes.[18] Accordingly, occurrence of carotid plaque rupture or hemorrhage with‐ out symptomatic manifestation seems likely.The frequency of plaque hemorrhage and plaque disruption varied greatly among the various series from both symptomatic and asymptomatic specimens In a review of several studies,[25,37,42-46] Fisher et al observed that the pooled frequency of plaque hemorrhage and rupture demonstrated a significant‐ ly increased frequency in the symptomatic group. However,pooling data from multiple sources when methods of analysis are different (histologicvs macroscopic) is hazardous. [47] Therefore studies in which only macroscopic assessment was performed[25,37,48-53] must be discarded. Some authors stress that IPH indicates only the severity of atherosclero‐ sis;[50,51,54-57] others suggest IPH has a direct role in pathogenesis of transient ischemic attack or stroke. [25,35,44,46,57] When most studies are considered, the incidence of IPH in symptomatic and asymptomatic disease spreads considerably In the symptomatic group, incidence varied from 17% to 97%, compared with 2% to 91% in the asymptomatic group. In the European Carotid Plaque Study, [58] a high incidence of IPH was observed in symptomatic (94%) and asymptomatic (71%) groups A higher incidence of IPH was reported in patients without symptoms.[55,59,60] Lennihan et al[54] scored the occurrence of IPH only in patients with symptoms, and found ipsilateral symptoms in 57% of patients with IPH and 65% of patients without IPH, indicating little difference between the two groups. IPH seems to be more common in plaques causing high-grade stenosis.[47,54,55] Carr et al[52] found patients with symptomatic plaques to have more frequent plaque rupture, fibrous cap thinning, and cap foam cell infiltration, compared with patients with asympto‐ matic plaques. IPH was also seen in all specimens from symptomatic specimens and in 68% of asymptomatic specimens. However, this study included too few patients to be signifi‐ cant. Despite a close relationship between IPH and symptoms,[37,61-63] and carotid plaque rupture, thrombosis, and symptoms, [25,60,61] it has also been claimed that patients with

course of a carotid plaque.[18,30,37,38]

44 Carotid Artery Disease - From Bench to Bedside and Beyond

Patients with asymptomatic carotid artery stenosis should be screened for other treatable risk factors for stroke with institution of appropriate lifestyle changes and medical therapy (Class I; Level of Evidence C).


Other points to consider is the necessity of interventionally treating an asymptomatic carotid artery disease are: age 80 years or less, life expectancy higher tan 5 years, hemispheric hypoperfusion, significant intracerebral vascular disease,unstable carotid plaque, rapid progression of the stenoses, presence of silent cerebral infarcts, neck radiotherapy and the necessity of a coronary by pass surgery. [66-74]

unstable.[25,28,53] Embolization of fibrin and platelets and/or atherosclerotic material from

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As was mentioned, Geroulakos et al[81] classified ultrasonographic carotid plaques in 5 different types of stenosis, and correlated plaque type with symptomatology (not with pathology), showing the predominance of echolucent plaques in symptomatic patients with stenosis > 70 percent (see below) From the histologic point of view it was found that 50 % of the IPH had connections with the lumen while 20 % had not.[30] Lusby et al[25] showed that "haemorrhage in carotid atheromatous plaques plays a unique and major role in the develop‐ ment of cerebrovascular disease". IPH was not only identified in most symptomatic patients but also a close relationship was established between the onset of symptoms and the presence of plaque haemorrhage. Seeger et al[81-85] reported that the composition of plaques from symptomatic patients is significantly different from those asymptomatic. The former contains

Johnson et al [86] classified asymptomatic plaques according to ultrasonographic characteris‐ tics into calcified, dense and soft. At the end of a 3 year follow-up a large proportion of asymptomatic patients with soft plaques had become symptomatic, while a small proportion of those with calcified plaques have developed symptoms. Hennerici et al [87] reported that patients with fibrous carotid plaques had a tendency to remain stable while plaque progression was common in those with soft and complex calcified plaques. Spontaneous regression of minor carotid atheroma occurred in soft plaques corresponding to a reduction in plaque

Despite that currently the presence of symptoms and percentage of luminal narrowing remain the most useful predictors of transitory ischemic cerebral attacks or stroke risk, [3,75,88,89] there is a body of evidence that plaque morphology is crucial in the development of its natural

Regarding the relationship of IPH with a higher prevalence of symptoms or hemorrhagic stroke, the results are contradictory. [23-64] However, current guidelines recommend report‐ ing the plaque structure in question and that in occasions define therapeutic behaviors. [82-83]

There are several reasons that make knowledge of plaques structure very important. It is well known that fibrous plaques, are predominantly collagen in content, showing a highly echo‐ genic quality and being generally homogeneous in texture. When lipid content of the plaque increased, the plaque turns more echolucent. [84] Complex plaques protrude more frequently into the lumen presenting high incidence of surface irregularities and ulcers. [60] Several authors found that the incidence of IPH, histologically assessed, in symptomatic carotid stenosis is higher than 90 %. [25,44,53,99] Imparato et al, prospectively studied 376 carotid artery plaques concluding that IPH was strongly associated with the presence of cerebrovas‐ cular symptoms and it was the main characteristic of the carotid plaque that correlated statistically with the presence of symptoms. [44] O´Donnel theorized that IPH is the most

more total lipid and cholesterol, and less collagen and calcium.

volume while fibrous and calcified plaques did not regress. [87]

common morphologic characteristic in symptomatic patients. [60]

the plaque itself will continue.

history.

As it can be seen, up to date criterium for percentage stenoses in this group of patients are higher than in the ACAS study (60%). [75]

Finally and taking into consideration the mechanisms of atherosclerosis: cells component behavior, IPH, biology and gene expression, it can be seen in the literature a new tendency of treatment in animal models. However, attention should therefore focus on the processes of plaque breakdown andt hrombus formation in humans, whereas the use of animal models should probably be reserved for studying the function of particular genes and for investigating isolated features of plaques,such as the relationshipbetween cap thickness and plaque stability. [76] In this connection, Peter et al [77] described a ApoE(-/-) mice mouse model reflecting human atherosclerotic plaque instability in which atorvastatinwas used aimed at preventing plaque rupture. They concluded that distinctly expressed genes andmicroRNAscan be linked to plaque instability.On the other hand, Forte et al described the role of polyamines in reducing carotid arteriotomy-induced (re)stenosis s in vitro and in a rat model suggesting a novel therapeutic approach for this pathophysiological process. [78]
